Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria

Aims  The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods  In part I of the study three different artemotil dose regimens were explored in three groups of 6–9 patients for dose finding: 3.2 mg kg−1 on day 0 and 1.6 mg kg−1 on days 1–4 (treatment A), 1.6 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment B), 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20–22 patients with standard i.m. artemether treatment: 3.2 mg kg−1 on day 0 and 0.8 mg kg−1 on days 1–4 (treatment R). Results  Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions  The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.